BACKGROUND

Overweight and obesity is a significant health concern during pregnancy. Our aim was to investigate the effect of providing antenatal dietary and lifestyle advice to women who are overweight or obese on components of maternal diet and physical activity.

METHODS

We conducted a randomised controlled trial, in which pregnant women with a body mass index≥25 kg/m2, and singleton gestation between 10(+0) to 20(+0) weeks were recruited and randomised to Lifestyle Advice (involving a comprehensive dietary and lifestyle intervention over their pregnancy) or Standard Care. Within the intervention group, we conducted a nested randomised trial in which a subgroup of women were further randomised to receive access to supervised group walking sessions in addition to the standard information presented during the intervention contacts (the Walking group) or standard information only. The outcome measures were maternal dietary intake, (including food groups, macronutrient and micronutrient intake, diet quality (using the Healthy Eating Index; HEI), dietary glycaemic load, and glycaemic index) and maternal physical activity. Women completed the Harvard Semi-Structured Food Frequency Questionnaire, and the Short Questionnaire to Assess Health-enhancing Physical Activity (SQUASH), at trial entry, 28 and 36 weeks' gestational age, and 4 months postpartum. Analyses were performed on an intention-to-treat basis, using linear mixed effects models with adjustment for the stratification variables.

RESULTS

Women randomised to Lifestyle Advice demonstrated a statistically significant increase in the number of servings of fruit and vegetables consumed per day, as well as increased consumption of fibre, and reduced percentage energy intake from saturated fats (P<0.05 for all). Maternal HEI was significantly improved at both 28 (73.35±6.62 versus 71.86±7.01; adjusted difference in means 1.58; 95% CI 0.89 to 2.27; P<0.0001) and 36 (72.95±6.82 versus 71.17±7.69; adjusted difference in means 1.77; 95% CI 1.01 to 2.53; P<0.0001) weeks. There were no differences in dietary glycaemic index or glycaemic load. Women randomised to Lifestyle Advice also demonstrated greater total physical activity (adjusted difference in means 359.76 metabolic equivalent task units (MET) minutes/week; 95% CI 74.87 to 644.65; P=0.01) compared with women receiving Standard Care. The supervised walking group was poorly utilised.

CONCLUSIONS

For women who are overweight or obese, antenatal lifestyle advice improves maternal diet and physical activity during pregnancy. Please see related articles: http://www.biomedcentral.com/1741-7015/12/163 and http://www.biomedcentral.com/1741-7015/12/201.

BACKGROUND

Australian and New Zealand Clinical Trials Registry ( ACTRN12607000161426).

Data in the biological, chemical, and clinical domains are accumulating at ever-increasing rates and have the potential to accelerate and inform drug development in new ways. Challenges and opportunities now lie in developing analytic tools to transform these often complex and heterogeneous data into testable hypotheses and actionable insights. This is the aim of computational pharmacology, which uses in silico techniques to better understand and predict how drugs affect biological systems, which can in turn improve clinical use, avoid unwanted side effects, and guide selection and development of better treatments. One exciting application of computational pharmacology is drug repurposing-finding new uses for existing drugs. Already yielding many promising candidates, this strategy has the potential to improve the efficiency of the drug development process and reach patient populations with previously unmet needs such as those with rare diseases. While current techniques in computational pharmacology and drug repurposing often focus on just a single data modality such as gene expression or drug-target interactions, we argue that methods such as matrix factorization that can integrate data within and across diverse data types have the potential to improve predictive performance and provide a fuller picture of a drug's pharmacological action. WIREs Syst Biol Med 2016, 8:186-210. doi: 10.1002/wsbm.1337 For further resources related to this article, please visit the WIREs website.

The internal structure of the cerebellum reflects an intriguing paradox; its cytoarchitecture is relatively simple and repeated throughout, yet the connections between its neurons are wired into a complex array of gene expression domains and functional circuits. The developmental mechanisms that coordinate the establishment of cerebellar structure and circuitry provide a powerful model for understanding how functional brain networks are formed. Two primary germinal zones generate the cells that make up the cerebellum. Each zone expresses a specific set of genes that establish the cell lineages within the cerebellar anlage. Then, cohorts of differentiated projection neurons and interneuron progenitors migrate into the developing cerebellum. Thereafter, a number of remarkable patterning events occur including transformation of the smooth cerebellar surface into an intricately patterned series of folds, formation of three distinct cellular layers, and the demarcation of parasagittal gene expression domains. Together, these structural and molecular organizations are thought to support the proper connectivity between incoming afferent projections and their target cells. After birth, genetic programs and neural activity repattern synaptic connections into topographic neural networks called modules, which are organized around a longitudinal zone plan and are defined by their molecular, anatomic, and functional properties. WIREs Dev Biol 2013, 2:149-164. doi: 10.1002/wdev.65 For further resources related to this article, please visit the WIREs website.

Stress can affect cognition in many ways, with the outcome (i.e., facilitating or impairing) depending on a combination of factors related to both stress and the cognitive function under study. Among the factors identified as particularly relevant to define the cognitive effects of stress are the intensity or magnitude of stress, its origin (i.e., whether triggered by the task or externally), and its duration (i.e., whether acute or chronically delivered). At the cognitive end, the specific cognitive operation (e.g., implicit or explicit memory, long-term or working memory, goal-directed or habit learning) and information processing phases (e.g., learning, consolidation, and retrieval) are essential as well to define stress effects. The emerging view is that mild stress tends to facilitate cognitive function, particularly in implicit memory or simple declarative tasks or when the cognitive load is not excessive. Exposure to high or very high stress acutely (whether elicited by the cognitive task or experienced before being trained or tested in the task) or chronically impairs the formation of explicit memories and, more generally, of those that require complex, flexible reasoning (as typically observed for hippocampus- and prefrontal cortex-related functions) while improving performance of implicit memory and well-rehearsed tasks (as reported for amygdala-dependent conditioning tasks and for striatum-related processes). In addition to these general principles, there are important individual differences in the cognitive impact of stress, with gender and age being particularly influencing factors. WIREs Cogn Sci 2013, 4:245-261. doi: 10.1002/wcs.1222 For further resources related to this article, please visit the WIREs website.

Determining the toxicity of chemicals is necessary to identify their harmful effects on humans, animals, plants, or the environment. It is also one of the main steps in drug design. Animal models have been used for a long time for toxicity testing. However, in vivo animal tests are constrained by time, ethical considerations, and financial burden. Therefore, computational methods for estimating the toxicity of chemicals are considered useful. In silico toxicology is one type of toxicity assessment that uses computational methods to analyze, simulate, visualize, or predict the toxicity of chemicals. In silico toxicology aims to complement existing toxicity tests to predict toxicity, prioritize chemicals, guide toxicity tests, and minimize late-stage failures in drugs design. There are various methods for generating models to predict toxicity endpoints. We provide a comprehensive overview, explain, and compare the strengths and weaknesses of the existing modeling methods and algorithms for toxicity prediction with a particular (but not exclusive) emphasis on computational tools that can implement these methods and refer to expert systems that deploy the prediction models. Finally, we briefly review a number of new research directions in in silico toxicology and provide recommendations for designing in silico models. WIREs Comput Mol Sci 2016, 6:147-172. doi: 10.1002/wcms.1240 For further resources related to this article, please visit the WIREs website.

BACKGROUND

Although stroke is acknowledged as a long-term condition, population estimates of outcomes longer term are lacking. Such estimates would be useful for planning health services and developing research that might ultimately improve outcomes. This burden of disease study provides population-based estimates of outcomes with a focus on disability, cognition, and psychological outcomes up to 10 y after initial stroke event in a multi-ethnic European population.

RESULTS

Data were collected from the population-based South London Stroke Register, a prospective population-based register documenting all first in a lifetime strokes since 1 January 1995 in a multi-ethnic inner city population. The outcomes assessed are reported as estimates of need and included disability (Barthel Index <15), inactivity (Frenchay Activities Index <15), cognitive impairment (Abbreviated Mental Test < 8 or Mini-Mental State Exam <24), anxiety and depression (Hospital Anxiety and Depression Scale >10), and mental and physical domain scores of the Medical Outcomes Study 12-item short form (SF-12) health survey. Estimates were stratified by age, gender, and ethnicity, and age-adjusted using the standard European population. Plots of outcome estimates over time were constructed to examine temporal trends and sociodemographic differences. Between 1995 and 2006, 3,373 first-ever strokes were registered: 20%-30% of survivors had a poor outcome over 10 y of follow-up. The highest rate of disability was observed 7 d after stroke and remained at around 110 per 1,000 stroke survivors from 3 mo to 10 y. Rates of inactivity and cognitive impairment both declined up to 1 y (280/1,000 and 180/1,000 survivors, respectively); thereafter rates of inactivity remained stable till year eight, then increased, whereas rates of cognitive impairment fluctuated till year eight, then increased. Anxiety and depression showed some fluctuation over time, with a rate of 350 and 310 per 1,000 stroke survivors, respectively. SF-12 scores showed little variation from 3 mo to 10 y after stroke. Inactivity was higher in males at all time points, and in white compared to black stroke survivors, although black survivors reported better outcomes in the SF-12 physical domain. No other major differences were observed by gender or ethnicity. Increased age was associated with higher rates of disability, inactivity, and cognitive impairment.

CONCLUSIONS

Between 20% and 30% of stroke survivors have a poor range of outcomes up to 10 y after stroke. Such epidemiological data demonstrate the sociodemographic groups that are most affected longer term and should be used to develop longer term management strategies that reduce the significant poor outcomes of this group, for whom effective interventions are currently elusive. Please see later in the article for the Editors' Summary.

BACKGROUND

There is a paucity of data on the health care costs of antiretroviral therapy (ART) programmes in Africa. Our objectives were to describe the direct heath care costs and establish the cost drivers over time in an HIV managed care programme in Southern Africa.

RESULTS

We analysed the direct costs of treating HIV-infected adults enrolled in the managed care programme from 3 years before starting non-nucleoside reverse transcriptase inhibitor-based ART up to 5 years afterwards. The CD4 cell count criterion for starting ART was <350 cells/microl. We explored associations between variables and mean total costs over time using a generalised linear model with a log-link function and a gamma distribution. Our cohort consisted of 10,735 patients (59.4% women) with 594,497 mo of follow up data (50.9% of months on ART). Median baseline CD4+ cell count and viral load were 125 cells/microl and 5.16 log(10) copies/ml respectively. There was a peak in costs in the period around ART initiation (from 4 mo before until 4 mo after starting ART) driven largely by hospitalisation, following which costs plateaued for 5 years. The variables associated with changes in mean total costs varied with time. Key early associations with higher costs were low baseline CD4+ cell count, high baseline HIV viral load, and shorter duration in HIV care prior to starting ART; whilst later associations with higher costs were lower ART adherence, switching to protease inhibitor-based ART, and starting ART at an older age.

CONCLUSIONS

Drivers of mean total costs changed considerably over time. Starting ART at higher CD4 counts or longer pre-ART care should reduce early costs. Monitoring ART adherence and interventions to improve it should reduce later costs. Cost models of ART should take into account these time-dependent cost drivers, and include costs before starting ART. Please see later in the article for the Editors' Summary.

BACKGROUND

The relationship between health professionals and the pharmaceutical industry has become a source of controversy. Physicians' attitudes towards the industry can form early in their careers, but little is known about this key stage of development.

RESULTS

We performed a systematic review reported according to PRISMA guidelines to determine the frequency and nature of medical students' exposure to the drug industry, as well as students' attitudes concerning pharmaceutical policy issues. We searched MEDLINE, EMBASE, Web of Science, and ERIC from the earliest available dates through May 2010, as well as bibliographies of selected studies. We sought original studies that reported quantitative or qualitative data about medical students' exposure to pharmaceutical marketing, their attitudes about marketing practices, relationships with industry, and related pharmaceutical policy issues. Studies were separated, where possible, into those that addressed preclinical versus clinical training, and were quality rated using a standard methodology. Thirty-two studies met inclusion criteria. We found that 40%-100% of medical students reported interacting with the pharmaceutical industry. A substantial proportion of students (13%-69%) were reported as believing that gifts from industry influence prescribing. Eight studies reported a correlation between frequency of contact and favorable attitudes toward industry interactions. Students were more approving of gifts to physicians or medical students than to government officials. Certain attitudes appeared to change during medical school, though a time trend was not performed; for example, clinical students (53%-71%) were more likely than preclinical students (29%-62%) to report that promotional information helps educate about new drugs.

CONCLUSIONS

Undergraduate medical education provides substantial contact with pharmaceutical marketing, and the extent of such contact is associated with positive attitudes about marketing and skepticism about negative implications of these interactions. These results support future research into the association between exposure and attitudes, as well as any modifiable factors that contribute to attitudinal changes during medical education. Please see later in the article for the Editors' Summary.

BACKGROUND

Despite the proven efficacy of prescription regimens in reducing disease symptoms and preventing or minimizing complications, poor medication adherence remains a significant public health problem. Medicare beneficiaries have high rates of chronic illness and prescription medication use, making this population particularly vulnerable to nonadherence. Failure to fill prescribed medication is a key component of nonadherence.

OBJECTIVE

To (1) determine the rates of self-reported failure to fill at least 1 prescription among a sample of Medicare beneficiaries in 2004, (2) identify the reasons for not filling prescribed medication, (3) examine the characteristics of Medicare beneficiaries who failed to fill their prescription(s), and (4) identify the types of medications that were not obtained.

METHODS

The study is a secondary analysis of the 2004 Medicare Current Beneficiary Survey (MCBS), an ongoing national panel survey conducted by the Centers for Medicare & Medicaid Services (CMS). Medicare beneficiaries living in the community (N = 14,464) were asked: "During the current year [2004], were there any medicines prescribed for you that you did not get (please include refills of earlier prescriptions as well as prescriptions that were written or phoned in by a doctor)?" Those who responded "yes" to this question (n = 664) were asked to identify the specific medication(s) not obtained. Rates of failure to fill were compared by demographic and income categories and for respondents with versus without self-reported chronic conditions, identified by asking respondents if they had ever been told by a doctor that they had the condition. Weighted population estimates for nonadherence were calculated using Professional Software for Survey Data Analysis for Multi-stage Sample Designs (SUDAAN) to account for the MCBS multistage stratified cluster sampling process. Unweighted counts of the prescriptions not filled by therapeutic class were calculated using Statistical Analysis Software (SAS).

RESULTS

In 2004, an estimated 1.6 million Medicare beneficiaries (4.4%) failed to fill or refill 1 or more prescriptions. The most common reasons cited for failure to fill were: "thought it would cost too much" (55.5%), followed by "medicine not covered by insurance" (20.2%), "didn't think medicine was necessary for the condition" (18.0%), and "was afraid of medicine reactions/contraindications" (11.8%). Rates of failure to fill were significantly higher among Medicare beneficiaries aged 18 to 64 years eligible through Social Security Disability Insurance (10.4%) than among beneficiaries aged 65 years or older (3.3%, P < 0.001). Rates were slightly higher for women than for men (5.0 vs. 3.6%, P = 0.001), for nonwhite than for white respondents (5.5% vs. 4.2%, P = 0.010), and for dually eligible Medicaid beneficiaries than for those who did not have Medicaid coverage (6.3% vs. 4.0% P = 0.001). Failure-to-fill rates were significantly higher among beneficiaries with psychiatric conditions (8.0%, P < 0.001); arthritis (5.2%, P < 0.001); cardiovascular disease (5.2%, P = 0.003); and emphysema, asthma, or chronic obstructive pulmonary disease (6.6%, P < 0.001) than among respondents who did not report those conditions, and the rate for respondents who reported no chronic conditions was 2.5%. Rates were higher for those with more self-reported chronic conditions (3.2%, 4.0%, 4.3%, and 5.9% for those with 1, 2, 3, and 4 or more conditions, respectively, P < 0.001). Among the prescriptions not filled (993 prescriptions indentified by 664 respondents), central nervous system agents, including nonsteroidal anti-inflammatory drugs, were most frequently identified (23.6%, n = 234), followed by cardiovascular agents (18.3%, n = 182) and endocrine/metabolic agents (6.5%, n = 65). Of the reported unfilled prescriptions, 8.1% were for antihyperlipidemic agents, 5.4% were for antidepressant drugs, 4.6% were for antibiotics, and 29.9% were for unidentified therapy classes.

CONCLUSIONS

Most Medicare beneficiaries fill their prescriptions, but some subpopulations are at significantly higher risk for nonadherence associated with unfilled prescriptions, including working-age beneficiaries, dual-eligible beneficiaries, and beneficiaries with multiple chronic conditions. Self-reported unfilled prescriptions included critical medications for treatment of acute and chronic disease, including antihyperlipidemic agents, antidepressants, and antibiotics.

BACKGROUND

Access to unpublished clinical study reports (CSRs) is currently being discussed as a means to allow unbiased evaluation of clinical research. The Institute for Quality and Efficiency in Health Care (IQWiG) routinely requests CSRs from manufacturers for its drug assessments. Our objective was to determine the information gain from CSRs compared to publicly available sources (journal publications and registry reports) for patient-relevant outcomes included in IQWiG health technology assessments (HTAs) of drugs.

RESULTS

We used a sample of 101 trials with full CSRs received for 16 HTAs of drugs completed by IQWiG between 15 January 2006 and 14 February 2011, and analyzed the CSRs and the publicly available sources of these trials. For each document type we assessed the completeness of information on all patient-relevant outcomes included in the HTAs (benefit outcomes, e.g., mortality, symptoms, and health-related quality of life; harm outcomes, e.g., adverse events). We dichotomized the outcomes as "completely reported" or "incompletely reported." For each document type, we calculated the proportion of outcomes with complete information per outcome category and overall. We analyzed 101 trials with CSRs; 86 had at least one publicly available source, 65 at least one journal publication, and 50 a registry report. The trials included 1,080 patient-relevant outcomes. The CSRs provided complete information on a considerably higher proportion of outcomes (86%) than the combined publicly available sources (39%). With the exception of health-related quality of life (57%), CSRs provided complete information on 78% to 100% of the various benefit outcomes (combined publicly available sources: 20% to 53%). CSRs also provided considerably more information on harms. The differences in completeness of information for patient-relevant outcomes between CSRs and journal publications or registry reports (or a combination of both) were statistically significant for all types of outcomes. The main limitation of our study is that our sample is not representative because only CSRs provided voluntarily by pharmaceutical companies upon request could be assessed. In addition, the sample covered only a limited number of therapeutic areas and was restricted to randomized controlled trials investigating drugs.

CONCLUSIONS

In contrast to CSRs, publicly available sources provide insufficient information on patient-relevant outcomes of clinical trials. CSRs should therefore be made publicly available. Please see later in the article for the Editors' Summary.

BACKGROUND

The clustering of metabolic and cardiovascular risk factors is known as metabolic syndrome (MetS). The risk of having MetS is strongly associated with increased adiposity and can be further modified by smoking behavior. Apolipoproteins (apo) associated with low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) may be altered in MetS. This study aimed to examine the association between smoking and the following parameters: MetS and its components, levels of apolipoproteins and estimated lipoprotein particle size, separately for men and women, and in different body mass index (BMI) classes.

METHODS

We included 24,389 men and 35,078 women aged between 18 and 80 years who participated in the LifeLines Cohort Study between December 2006 and January 2012; 5,685 men and 6,989 women were current smokers. Participants were categorized into three different body mass index (BMI) classes (BMI <25; BMI 25 to 30; BMI ≥30 kg/m²). MetS was defined according to the National Cholesterol Education Program's Adult Treatment Panel III (NCEP:ATPIII) criteria. Blood pressure, anthropometric and lipid measurements were rigorously standardized, and the large sample size enabled a powerful estimate of quantitative changes. The association between smoking and the individual MetS components, and apoA1 and apoB, was tested with linear regression. Logistic regression was used to examine the effect of smoking and daily tobacco smoked on risk of having MetS. All models were age adjusted and stratified by sex and BMI class.

RESULTS

Prevalence of MetS increased with higher BMI levels. A total of 64% of obese men and 42% of obese women had MetS. Current smoking was associated with a higher risk of MetS in both sexes and all BMI classes (odds ratio 1.7 to 2.4 for men, 1.8 to 2.3 for women, all P values <0.001). Current smokers had lower levels of HDL cholesterol and apoA1, higher levels of triglycerides and apoB, and higher waist circumference than non-smokers (all P <0.001). Smoking had no consistent association with blood pressure or fasting blood glucose. In all BMI classes, we found a dose-dependent association of daily tobacco consumption with MetS prevalence as well as with lower levels of HDL cholesterol, higher triglyceride levels and lower ratios of HDL cholesterol/apoA1 and, only in those with BMI <30, LDL cholesterol/apoB (all P <0.001).

CONCLUSIONS

Smoking is associated with an increased prevalence of MetS, independent of sex and BMI class. This increased risk is mainly related to lower HDL cholesterol, and higher triglycerides and waist circumference. In addition, smoking was associated with unfavorable changes in apoA1 and apoB, and in lipoprotein particle size. Please see related commentary: http://www.biomedcentral.com/1741-7015/11/196.

The relationship between inflammation and cancer has been recognized since the 17th century,1 and we now know much about the cells, cytokines and physiological processes that are central to both inflammation and cancer.2-9 Chronic inflammation can induce certain cancers,10-17 and solid tumors, in turn, can initiate and perpetuate local inflammatory processes that foster tumor growth and dissemination.5 ,18-20 Consequently, inflammatory pathways have been targeted in attempts to control cancer.21-23 Inflammation is a central aspect of the innate immune system's response to tissue damage or infection, and also facilitates the recruitment of circulating cells and antibodies of the adaptive immune response to the tissue. Components of the innate immune response carry out a robust, but sometimes overly-conservative response, sacrificing specificity for the sake of preservation. Thus, when innate immunity goes awry, it can have profound implications. How the innate and adaptive immune systems cooperate to neutralize pathogens and repair damaged tissues is still an area of intense investigation. Further, how these systems can respond to cancer, which arises from normal 'self' cells that undergo an oncogenic transformation, has profound implications for cancer therapy. Recently, immunotherapies that activate adaptive immunity have shown unprecedented promise in the clinic, producing durable responses and dramatic increases in survival rate in patients with advanced stage melanoma.24-26 Consequently, the relationship between cancer and inflammation has now returned to the forefront of clinical oncology. WIREs Syst Biol Med 2017, 9:e1370. doi: 10.1002/wsbm.1370 For further resources related to this article, please visit the WIREs website.

Organoids are in vitro-cultured three-dimensional structures that recapitulate key aspects of in vivo organs. They can be established from pluripotent stem cells and from adult stem cells, the latter being the subject of this review. Organoids derived from adult stem cells exploit the tissue regeneration process that is driven by these cells, and they can be established directly from the healthy or diseased epithelium of many organs. Organoids are amenable to any experimental approach that has been developed for cell lines. Applications in experimental biology involve the modeling of tissue physiology and disease, including malignant, hereditary, and infectious diseases. Biobanks of patient-derived tumor organoids are used in drug development research, and they hold promise for developing personalized and regenerative medicine. In this review, we discuss the applications of adult stem cell-derived organoids in the laboratory and the clinic. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 15 is January 24, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Controversy has surrounded the differentiation of Trypanosoma brucei gambiense from T. b. rhodesiense (causative agents of Gambian and Rhodesian sleeping sickness, respectively) almost from the moment they were named. In the light of recent findings from biochemical and immunological characterization studies, Wendy Gibson reviews the status of T. b. gambiense to see if there is now a consensus concerning its identity.

Identifying and scoring cancer markers plays a key role in oncology, helping to characterize the tumor and predict the clinical course of the disease. The current method for scoring immunohistochemistry (IHC) slides is labor intensive and has inherent issues of quantitation. Although multiple attempts have been made to automate IHC scoring in the past decade, a major limitation in these efforts has been the setting of the threshold for positive staining. In this report, we propose the use of an averaged threshold measure (ATM) score that allows for automatic threshold setting. The ATM is a single multiplicative measure that includes both the proportion and intensity scores. It can be readily automated to allow for large-scale processing, and it is applicable in situations in which individual cells are hard to distinguish. The ATM scoring method was validated by applying it to simulated images, to a sequence of images from the same tumor, and to tumors from different patient biopsies that showed a broad range of staining patterns. Comparison between the ATM score and manual scoring by an expert pathologist showed that both methods resulted in essentially identical scores when applied to these patient biopsies. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.

BACKGROUND

The effectiveness of prenatal treatment to prevent serious neurological sequelae (SNSD) of congenital toxoplasmosis is not known.

RESULTS

Congenital toxoplasmosis was prospectively identified by universal prenatal or neonatal screening in 14 European centres and children were followed for a median of 4 years. We evaluated determinants of postnatal death or SNSD defined by one or more of functional neurological abnormalities, severe bilateral visual impairment, or pregnancy termination for confirmed congenital toxoplasmosis. Two-thirds of the cohort received prenatal treatment (189/293; 65%). 23/293 (8%) fetuses developed SNSD of which nine were pregnancy terminations. Prenatal treatment reduced the risk of SNSD. The odds ratio for prenatal treatment, adjusted for gestational age at maternal seroconversion, was 0.24 (95% Bayesian credible intervals 0.07-0.71). This effect was robust to most sensitivity analyses. The number of infected fetuses needed to be treated to prevent one case of SNSD was three (95% Bayesian credible intervals 2-15) after maternal seroconversion at 10 weeks, and 18 (9-75) at 30 weeks of gestation. Pyrimethamine-sulphonamide treatment did not reduce SNSD compared with spiramycin alone (adjusted odds ratio 0.78, 0.21-2.95). The proportion of live-born infants with intracranial lesions detected postnatally who developed SNSD was 31.0% (17.0%-38.1%).

CONCLUSIONS

The finding that prenatal treatment reduced the risk of SNSD in infected fetuses should be interpreted with caution because of the low number of SNSD cases and uncertainty about the timing of maternal seroconversion. As these are observational data, policy decisions about screening require further evidence from a randomized trial of prenatal screening and from cost-effectiveness analyses that take into account the incidence and prevalence of maternal infection. Please see later in the article for the Editors' Summary.

BACKGROUND

In 2004, Afghanistan pioneered a balanced scorecard (BSC) performance system to manage the delivery of primary health care services. This study examines the trends of 29 key performance indicators over a 5-year period between 2004 and 2008.

RESULTS

Independent evaluations of performance in six domains were conducted annually through 5,500 patient observations and exit interviews and 1,500 provider interviews in >600 facilities selected by stratified random sampling in each province. Generalized estimating equation (GEE) models were used to assess trends in BSC parameters. There was a progressive improvement in the national median scores scaled from 0-100 between 2004 and 2008 in all six domains: patient and community satisfaction of services (65.3-84.5, p<0.0001); provider satisfaction (65.4-79.2, p<0.01); capacity for service provision (47.4-76.4, p<0.0001); quality of services (40.5-67.4, p<0.0001); and overall vision for pro-poor and pro-female health services (52.0-52.6). The financial domain also showed improvement until 2007 (84.4-95.7, p<0.01), after which user fees were eliminated. By 2008, all provinces achieved the upper benchmark of national median set in 2004.

CONCLUSIONS

The BSC has been successfully employed to assess and improve health service capacity and service delivery using performance benchmarking during the 5-year period. However, scorecard reconfigurations are needed to integrate effectiveness and efficiency measures and accommodate changes in health systems policy and strategy architecture to ensure its continued relevance and effectiveness as a comprehensive health system performance measure. The process of BSC design and implementation can serve as a valuable prototype for health policy planners managing performance in similar health care contexts. Please see later in the article for the Editors' Summary.

BACKGROUND

Heart failure places a significant burden on patients and health systems in high-income countries. However, information about its burden in low- and middle-income countries (LMICs) is scant. We thus set out to review both published and unpublished information on the presentation, causes, management, and outcomes of heart failure in LMICs.

RESULTS

Medline, Embase, Global Health Database, and World Health Organization regional databases were searched for studies from LMICs published between 1 January 1995 and 30 March 2014. Additional unpublished data were requested from investigators and international heart failure experts. We identified 42 studies that provided relevant information on acute hospital care (25 LMICs; 232,550 patients) and 11 studies on the management of chronic heart failure in primary care or outpatient settings (14 LMICs; 5,358 patients). The mean age of patients studied ranged from 42 y in Cameroon and Ghana to 75 y in Argentina, and mean age in studies largely correlated with the human development index of the country in which they were conducted (r = 0.71, p<0.001). Overall, ischaemic heart disease was the main reported cause of heart failure in all regions except Africa and the Americas, where hypertension was predominant. Taking both those managed acutely in hospital and those in non-acute outpatient or community settings together, 57% (95% confidence interval [CI]: 49%-64%) of patients were treated with angiotensin-converting enzyme inhibitors, 34% (95% CI: 28%-41%) with beta-blockers, and 32% (95% CI: 25%-39%) with mineralocorticoid receptor antagonists. Mean inpatient stay was 10 d, ranging from 3 d in India to 23 d in China. Acute heart failure accounted for 2.2% (range: 0.3%-7.7%) of total hospital admissions, and mean in-hospital mortality was 8% (95% CI: 6%-10%). There was substantial variation between studies (p<0.001 across all variables), and most data were from urban tertiary referral centres. Only one population-based study assessing incidence and/or prevalence of heart failure was identified.

CONCLUSIONS

The presentation, underlying causes, management, and outcomes of heart failure vary substantially across LMICs. On average, the use of evidence-based medications tends to be suboptimal. Better strategies for heart failure surveillance and management in LMICs are needed. Please see later in the article for the Editors' Summary.

A growing body of cognitive research uses sophisticated behavioral and neuroimaging measurements to demonstrate associations between family socioeconomic status (SES) and specific cognitive functions. We argue for the value in these kinds of studies of increased sophistication in the measurement and modeling of SES. With regard to measurement, SES combines several components, each of which represents distinct resources that might benefit children's cognitive development in different ways. Policy implications of studies using omnibus SES composites are problematic because there are no 'treatments' for enhancing overall SES, although policies abound for enhancing specific components of SES such as family income. Past literature offers guidance regarding how best to measure each of the SES components. With regard to modeling, we point out that the manipulability of economic, educational, and occupational components of SES varies, which provides opportunities for generating experimental or quasi-experimental variation in some components but not others. Evidence on the causal connections between SES components and child outcomes is summarized. Both experimental and quasi-experimental studies involving manipulation of family income have demonstrated consistent associations with a number of cognitive measures. Quasi-experimental increases in maternal education have also shown associations with child achievement. We end with a discussion of useful directions in SES-related cognitive research. WIREs Cogn Sci 2012, 3:377-386. doi: 10.1002/wcs.1176 For further resources related to this article, please visit the WIREs website.

Xonghong Xiao and colleagues analyze the challenge of antimicrobial resistance in China. A government strategy to promote rational use of antimicrobials in health care reduced antibiotic sales and percentage of prescriptions for antimicrobials for both hospitalized patients and outpatients, and offers insights to shape future initiatives. Please see later in the article for the Editors' Summary.

The spliceosome removes introns from messenger RNA precursors (pre-mRNA). Decades of biochemistry and genetics combined with recent structural studies of the spliceosome have produced a detailed view of the mechanism of splicing. In this review, we aim to make this mechanism understandable and provide several videos of the spliceosome in action to illustrate the intricate choreography of splicing. The U1 and U2 small nuclear ribonucleoproteins (snRNPs) mark an intron and recruit the U4/U6.U5 tri-snRNP. Transfer of the 5' splice site (5'SS) from U1 to U6 snRNA triggers unwinding of U6 snRNA from U4 snRNA. U6 folds with U2 snRNA into an RNA-based active site that positions the 5'SS at two catalytic metal ions. The branch point (BP) adenosine attacks the 5'SS, producing a free 5' exon. Removal of the BP adenosine from the active site allows the 3'SS to bind, so that the 5' exon attacks the 3'SS to produce mature mRNA and an excised lariat intron. Expected final online publication date for the Annual Review of Biochemistry, Volume 89 is June 22, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Categorical perception (CP) is the phenomenon by which the categories possessed by an observer influences the observers' perception. Experimentally, CP is revealed when an observer's ability to make perceptual discriminations between things is better when those things belong to different categories rather than the same category, controlling for the physical difference between the things. We consider several core questions related to CP: Is it caused by innate and/or learned categories, how early in the information processing stream do categories influence perception, and what is the relation between ongoing linguistic processing and CP? CP for both speech and visual entities are surveyed, as are computational and mathematical models of CP. CP is an important phenomenon in cognitive science because it represents an essential adaptation of perception to support categorizations that an organism needs to make. Sensory signals that could be linearly related to physical qualities are warped in a nonlinear manner, transforming analog inputs into quasi-digital, quasi-symbolic encodings. Copyright © 2009 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website.

Oligonucleotides (ONs) can interfere with biomolecules representing the entire extended central dogma. Antisense gapmer, steric block, spliceswitching ONs, and short interfering RNA drugs have been successfully developed. Moreover, antagomirs (antimicroRNAs), microRNA mimics, aptamers, DNAdecoys, DNAzymes, synthetic guide strands for CRISPR/Cas, and innate immunity-stimulating ONs are all in clinical trials. DNAtargeting, triplex-forming ONs and strand-invading ONs have made their mark on drug development research, but not yet as medicines. Both design and synthetic nucleic acid chemistry are crucial for achieving biologically active ONs. The dominating modifications are phosphorothioate linkages, base methylation, and numerous 2'-substitutions in the furanose ring, such as 2'-fluoro, O-methyl, or methoxyethyl. Locked nucleic acid and constrained ethyl, a related variant, are bridged forms where the 2'-oxygen connects to the 4'-carbon in the sugar. Phosphorodiamidate morpholino oligomers, carrying a modified heterocyclic backbone ring, have also been commercialized. Delivery remains a major obstacle, but systemic administration and intrathecal infusion are used for treatment of the liver and brain, respectively. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

BACKGROUND

Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men's smoking prevalence is among the world's highest.

RESULTS

We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged ≥45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan-accounting for ∼71% of Asia's total population. An approximately 1.44-fold (95% CI = 1.37-1.51) and 1.48-fold (1.38-1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CI = 14.3%-17.2%) and 3.3% (2.6%-4.0%) of deaths, respectively, in men and women aged ≥45 y in the seven countries/regions combined, with a total number of estimated deaths of ∼1,575,500 (95% CI = 1,398,000-1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: a 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged ≥45 y.

CONCLUSIONS

Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged ≥45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented. Please see later in the article for the Editors' Summary.